The Effect of the Creatine Analogue Beta-guanidinopropionic Acid on Energy Metabolism: A Systematic Review

Abstract

BackgroundCreatine kinase plays a key role in cellular energy transport. The enzyme transfers high-energy phosphoryl groups from mitochondria to subcellular sites of ATP hydrolysis, where it buffers ADP concentration by catalyzing the reversible transfer of the high-energy phosphate moiety (P) between creatine and ADP. Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. This substance is marked as safe for human use, but the effects are unclear. Therefore, we systematically reviewed the effect of beta-guanidinopropionic acid on energy metabolism and function of tissues with high energy demands.MethodsWe performed a systematic review and searched the electronic databases Pubmed, EMBASE, the Cochrane Library, and LILACS from their inception through March 2011. Furthermore, we searched the internet and explored references from textbooks and reviews.ResultsAfter applying the inclusion criteria, we retrieved 131 publications, mainly considering the effect of chronic oral administration of beta-guanidinopropionic acid (0.5 to 3.5%) on skeletal muscle, the cardiovascular system, and brain tissue in animals. Beta-guanidinopropionic acid decreased intracellular creatine and phosphocreatine in all tissues studied. In skeletal muscle, this effect induced a shift from glycolytic to oxidative metabolism, increased cellular glucose uptake and increased fatigue tolerance. In heart tissue this shift to mitochondrial metabolism was less pronounced. Myocardial contractility was modestly reduced, including a decreased ventricular developed pressure, albeit with unchanged cardiac output. In brain tissue adaptations in energy metabolism resulted in enhanced ATP stability and survival during hypoxia.ConclusionChronic beta-guanidinopropionic acid increases fatigue tolerance of skeletal muscle and survival during ischaemia in animal studies, with modestly reduced myocardial contractility. Because it is marked as safe for human use, there is a need for human data.

Creatine loading elevates the intracellular phosphorylation potential and alters adaptive responses of rat fast-twitch muscle to chronic low-frequency stimulation

“…First, hyperosmolarity did not occur in the present study or in our previous studies (Gallo et al 2006(Gallo et al , 2008. Second, ␤-GPA does not induce expression of "osmosensing" genes, even though it has a higher affinity for cellular uptake, accumulates as phosphorylated ␤-GPA, and has the potential to generate greater increases in osmolarity (Oudman et al 2013). Third, if Cr possessed the potential to directly regulate the expression of other gene families, then it follows that ␤-GPA should exert the same effect, but it does not.…”

A new cell-based assay to evaluate myogenesis in mouse myoblast C2C12 cells

“…To further confirm that this system reflects myogenesis and myofusion, we treated the cells with GPA and IGF1, which are known to promote myogenesis, and z-VAD-FMK, which is known to inhibit myofusion [16][17][18]. 10 ng/ml IGF1 facilitated and enhanced GFP signals, while 100 μM z-VAD-FMK reduced ( Fig.…”

The Myocardial Creatine Kinase System in the Normal, Ischaemic and Failing Heart

“…A number of creatine analogues have been shown to compete with creatine for cellular uptake at the CrT, but are poor substrates for the CK reaction [ 2 ]. Of these, the most commonly used is β-guanidinopropionic acid (β-GPA), see [ 15 ] for a recent systematic review. β-GPA can be given in chow or water, however, loss of creatine from the myocardium is a slow process (~2 % of the total creatine pool per day [ 16 ]), therefore β-GPA has to be chronically dosed over a period of weeks, which may allow time for substantive compensatory adaptations to develop (for examples see [ 17 , 18 ]).…”